Apoptosis is a genetically regulated mechanism for programmed cell death, which is important from embryogenesis throughout adult life. It eliminates cells that are not useful to the multicellular organism by mechanisms that are distinct from the mechanisms that kill cells due to injury, anoxia, etc. Apoptosis is initiated by a signal to the cell, which activates a cascade of reactions involving various protein factors and proteolytic enzymes. The very specialized proteases involved, called caspases, are normally present in proenzyme form, and are activated by a cleavage mechanism. They then hydrolyze specific proteins, which initiates disassembly of the cell. Textbook of Biochemistry with Clinical Correlations, 5th ed., pg. 23 (Thomas M. Devlin, ed., Wiley-Liss (2002)).
Different types of cells have different receptors that can be stimulated to initiate apoptosis; the specificity of these receptors is obviously critical to the survival of an organism, because it determines which cells survive and which die. Dysfunctions in the apoptosis machinery are associated with a variety of disorders including immune disorders, inflammatory conditions, malignancies, neurodegenerative diseases, and viral infections that affect the immune system. Id. See also TNF, Apoptosis and Autoimmunity. A Common Thread?, B. Beutler and F. Bazzoni, Blood Cells, Molecules, and Diseases, 24(10), 216-30 (1998) (electronic journal, available online at http://www.scripps.edu/bcmd/).
Apoptosis has been described as a systematic process for eliminating unneeded or defective cells to maintain balance. C. B. Thompson, Science, vol. 267, 1456-61 (1995). Thus apoptosis provides a mechanism which could also be useful to eliminate defective cells such as malignancies if it could be selectively triggered in those cells. Tumor necrosis factor (TNF), a cytokine which selectively initiates apoptosis in tumor cells, demonstrated that treatment of cancer could in theory be accomplished with this approach, and efforts related to TNF continue, often focused on ways to control production of cytokines.
A substance referred to as T4 immune stimulating factor (TISF) has been identified and described recently due to its immune-stimulating activities. U.S. Pat. No. 5,616,554. TISF is alternatively referred to as Epithyme™ and as S-Celergin at times herein and in other references. It is one of a number of factors that have been described which stimulate various stages of CD4+ lymphocyte development. TISF stimulates a normally unresponsive population of cells at a later stage of the development process, while a different factor stimulating an earlier stage of the process is described, for example, in Beardsley, et al., PNAS 80: 6005 (1983).
TISF is a polypeptide that is typically glycosylated. It “stimulates, enhances or regulates cell-mediated immune responsiveness” by stimulating mature T-lymphocytes as described in U.S. Pat. No. 5,616,554. It is thus able to enhance the immune response of animals to infectious agents and to some malignancies. Id. In addition, TISF has been reported to promote hematopoiesis, or blood cell development, possibly by its ability to stimulate CD4+ lymphocytes. U.S. application Ser. No. 10/938,451. Thus in cats having feline immunodeficiency virus or feline leukemia virus infections, treatment with TISF increased lymphocyte counts, and also increased red blood cell, platelet and granulocyte levels. Id.
Cytokines, broadly defined, are cell-derived hormone-like peptides that regulate cellular replication, differentiation, or activation related to defense and/or repair of the host organism. Thus based on its activities described above, TISF may be considered a cytokine, like interferon, TNF, and the interleukins. However, as described in U.S. Pat. No. 5,616,554, TISF is distinct from the known cytokines.
Surprisingly in light of its ability to stimulate hematopoiesis, it has now been found that TISF is also capable of initiating apoptosis in some cell populations, including certain types of blood cells. In particular, it has been found that TISF selectively causes cell death or cessation of tissue growth in aberrant T-cells, such as lymphoma cells, lymphocytes that carry HIV virus, and leukemic cells. While reported to be capable of stimulating an immune response that could in theory target malignant cells, see U.S. Pat. No. 5,616,554, it is surprising to find that TISF can cause cell death selectively in compromised T-cells in the absence of any immune response, as demonstrated by in vitro experiments.
The present invention relates to methods of using TISF to treat disorders characterized by production, development, or activity of aberrant T-cells. Because it operates by a mechanism independent of the stimulation of the immune response previously associated with TISF, it provides methods to treat such conditions in immune-compromised individuals where a treatment relying on stimulation of the subject's immune response would not be expected to work well. For example, it is especially well suited to the treatment of subjects having an immune disorder such as HIV and treatment of subjects who are concurrently receiving immune-suppression drugs.
Each reference cited herein is incorporated by reference in its entirety. No citation of any document is an admission that such document constitutes prior art to this application.